Anti-inflammatory effects: Folmer et al. suggested that kavain and flavokavains A and B may play a role in reducing inflammation by regulating inhibition of nuclear factor kappaB (NF-kappaB) and inhibiting the degradation of other pathways.2

Anxiolytic properties: Kava extract produced statistically significant dose-dependent anxiolytic-like behavioral changes in both assays of anxiolysis in mice.14 Kava extracts produce significant murine anxiolytic-like behavioral changes and sedation that are not mediated through the benzodiazepine binding site on the GABA(A) receptor complex.14 The results of one animal study involving chicks suggest that dihydrokavain may be necessary and sufficient in mediating the anxiolytic properties of kava extract.24 Kava may selectively act on limbic structures, promoting anxiolysis without sedation.10 (+/-)-Kavain, one of the main active components of kava, may effectively modulate excitatory signals in the hippocampus of guinea pigs.25

CYP450 effects: Kava is known to have P450 1A2 inhibiting activity.26 Kava extracts have also induced CYP3A4 and activated human pregnane X receptor (PXR).27 Ma et al. proposed that the induction of CYP3A23 by dihydromethysticin and desmethoxyyangonin involves transcription activation, probably through a PXR-independent or PXR-involved indirect mechanism.

Hepatic effects: Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation.5 Whitton et al. found that aqueous extracts contain glutathione, which has the potential to react with the kava lactones to provide protection against hepatotoxicity, especially when detoxification pathways are saturated.6 Based on a case report, the simultaneous intake of St. John's wort may potentiate the toxicity of kavapyrones. However, Musch et al. have also noted that an immune-mediated mechanism for hepatotoxicty in this case induced by kava, cannot be completely ruled out.8 Furthermore, an unpublished analysis of the in vitro, in vivo, and clinical data shows that kava and its kava lactones are not predictable hepatotoxins.28 Recent studies in rats found that the aqueous extract of kava does not affect liver function tests.29 It is conceivable that different methods of preparation (alcohol, water, or acetonic extraction) yield different kava alkaloids.9 Chronic consumption of traditionally prepared kava beverages by regular kava beverage consumers was associated with an elevation of GGT in 65% of the kava drinkers versus 26% in the controls (p=0.005).7 ALP was elevated in 23% of kava drinkers versus 3% in the controls (p=0.053).

Neurologic effects: Kava extract has exhibited neuroprotective activity, which was probably mediated by its constituents methysticin and dihydromethysticin.4 Pyrones have been noted for their anticonvulsive, spasmolytic, and anti-mycotic effects, as well as synergistic hypnotic (barbiturate), analgesic, and local anesthetic effects.30,31,32,33,34,35,36,37 Pyrones exhibit neuroprotective4 and "recovery-supporting" effects on neurological deficits after cerebral infarction in animals.38 These effects have been attributed to calcium channel agonism39,40, sodium channel blocking41,1,42, inhibition of monoamine oxidase16, and inhibition of noradrenaline uptake43. In rats, kava does not appear to interact with benzodiazepine/GABA receptors.44 ,45 Kava seems to facilitate GABA transmission K.11,46 Neuro-physiologic studies with EEG have demonstrated similar activity of kava to GABA agonists.46,11 Interactions with glutamate47, dopamine3, noradrenaline43, serotonin3,39 ,40, and their respective receptors may mediate the anxiolytic effect of kava. Neither high single doses nor chronic administration of kavain, from the lipophilic fraction of kava, alters dopaminergic or serotonergic tissue levels in rats.48 Therefore, dopaminergic or serotonergic effects may reside in the water-soluble fraction of kava.49,50

Oncologic effects: Kava's analgesic effect is not antagonized by naloxone13,51, suggesting a mechanism unrelated to opiate receptors. In an animal model, tolerance and dependence formation have not been demonstrated52. Melanogenesis stimulation activity of aqueous ethanolic extracts obtained from several different parts of five Piper species, namely Piper longum, P. kadsura, P. methysticum, P. betle, and P. cubeba, were examined by using cultured murine B16 melanoma cells.53 Among them, the extract of P. methysticum rhizome showed potent stimulatory effect on melanogenesis as did P. nigrum leaf extract. Activity-guided fractionation of kava extract led to the isolation of two active kavalactones, yangonin and 7,8-epoxyyangonin, along with three inactive kavalactones, 5,6-dehydrokawain, (+)-kawain and (+)-methysticin, and a glucosylsterol, daucosterin. 7,8-Epoxyyangonin showed a significant stimulatory effect on melanogenesis in B16 melanoma cells. Yangonin exhibited a weak melanogenesis stimulation activity.

Pharmacodynamics/Kinetics:

A psychophysiologic study of kavain (Klinge Pharma, Munich, Germany) found pharmacodynamic peaks at 1-2 hours and eight hours, suggesting active metabolites. Peak levels occurred at 1.8 hours, with an elimination half-life of approximately nine hours and a distribution half-life of 50 minutes.12

Absorption: Absorption of kava root extracts may be faster than absorption of isolated lactones.

Metabolism: In a study of the metabolism of several kava lactones in male rats, it was observed that about one-half of the 400mg/kg dose of dihydrokavain administered was found in the urine in 48 hours.54 About two-thirds of this was hydroxylated metabolites. The remaining one-third consisted of metabolites formed by the catabolism of the kava lactone and also included hippuric acid. The metabolites of the other kava lactones have also been characterized by analyzing the urine samples from rats.

Excretion: Metabolites and unchanged lactones of kava are excreted in human urine and feces.55

Kava, and other herbs that have the potential to modulate the activity of drug-metabolizing enzymes (e.g., garlic, ginkgo, echinacea, and stjohnswort, may participate in pharmacokinetic interactions with anticancer drugs.15

Bioavailability: In vitro, kavalactones are potentially bioavailable because they all readily crossed the Caco-2 monolayers with apparent permeabilities increasing from 42 x 10(-6) cm/s and most exhibiting more than 70% crossing within 90min.56 Matthias et al. found that the differences in their bioavailability were not all related to kavalactone structural differences, however, because it appears co-extracted compounds may also affect the bioavailability.